We have undertaken investigations to characterize the molecular genetic basis of the pathogenesis of lymphoproliferative disorders and Hodgkin's disease. By DNA hybridization analysis, our investigations have demonstrated the existence of "benign clonal lymphadenopathy" and the evolution of malignant transformation to high grade lymphoma. The significance of this discovery, from a diagnostic standpoint, is that monoclonality is not necessarily tantamount to malignancy. We have further applied genomic blot hybridizations to analyze the use of specific variable genes of the T cell receptor gamma locus. Notably, gamma variable genes are not selected during a wide variety of human immune responses and immunodeficiency disorders. The defective mutants we have developed of the early T cell line, CEM, demonstrate a single critical step on T cell development surrounding the regulation of T cell receptor alpha gene transcription. To determine the origins of Hodgkin's disease, we have molecularly cloned the rearranged immunoglobulin heavy and T cell receptor beta genes from a Hodgkin's cell line. By sequence analysis, we can now investigate whether Hodgkin's cells have undergone chromosomal rearrangements as a key step in their malignant transformation. Our molecular genetic investigations of rearranged genes in Hodgkin's disease has now been expanded to include several cell lines and primary cases. This approach will enable us to uncover common molecular pathologies in Hodgkin's disease.